Chemical and Physical Mechanisms of Wound Detection

伤口检测的化学和物理机制

• 批准号: 10400094
• 负责人: Philipp Michael Niethammer
• 金额: $ 70.8万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10400094
• 关键词: Acute; Animals; Arachidonic Acids; Area; Biological; Biology; Biophysics; Bone Regeneration; Cells; Chemicals; Chronic; Detection; Diffuse; Disease; Epithelial; Failure; Funding; Growth Factor; Hydrogen Peroxide; Image Analysis; Immune system; Infection; Inflammation; Inflammatory Response; Injury; Leukocytes; Malignant Neoplasms; Mammals; Mediating; Medical; Molecular; Natural regeneration; Nuclear Envelope; Organism; Pathway interactions; Process; Resolution; Scheme; Signal Transduction; Tissues; Vision; Work; Wound Infection; Wound models; Zebrafish; animal tissue; cytokine; extracellular; flexibility; healing; interdisciplinary approach; interest; intravital imaging; mathematical model; mechanotransduction; novel therapeutic intervention; novel therapeutics; rapid detection; real-time images; repaired; response; response to injury; skin fibrosis; wound; wound closure; wound healing; wound response

Project Summary Rapid detection and response to injury is essential for the survival of all organisms. In animals, wounded tissues must quickly heal and locally regenerate. Failure in wound detection causes acute and chronic conditions ranging from poorly healing wounds and infections to chronically inflamed skins, fibrosis and cancer. Although the exe- cution mechanisms of wound healing (involving cytokines, growth factors, etc.) have been extensively studied, its initiation mechanisms remain little understood. My vision is to develop a genetically and physically plau- sible model of wound detection. There is a fundamental gap in understanding of how wounds are initially detected, and how the first wound signals rapidly transmit information on injury over tissue-scale dis- tances to faraway leukocytes, epithelial, and other cells that participate in healing. I study wound detection in live zebrafish whose wound responses and immune system resemble those of mam- mals yet are better amenable to high-resolution, real-time imaging at high animal throughputs. To this end, my lab combines quantitative intravital imaging with unbiased computational image analysis and various interdisci- plinary approaches ranging from biophysics to mathematical modeling. Over a decade, I have identified three chemical and one physical wound signals: hydrogen peroxide (H2O2), extracellular ATP (eATP), arachidonic acid (AA), and nuclear membrane tension. These discoveries triggered new activity in an old field. Yet, critical mech- anistic gaps remain: How is eATP sensed to mediate rapid wound closure, and how does it instruct faraway cells although it is rapidly broken down in the tissue and cannot diffuse far from a wound? How are H2O2 and AA signals integrated to mediate rapid inflammatory responses to wounds? Wound signals cause inflammation- do they also resolve it? How is wound mechanotransduction regulated on the molecular and cell biological level? These questions are of high basic biological interest, and the pathways they concern are major disease regula- tors. Answering them over the next five years can pave way for novel therapeutic approaches. My work on wound signaling has opened the door to other areas of biology where analogous mechanisms may drive medically important processes, such as infection responses, cancer and bone regeneration/remodeling. Although the primary focus of my group will remain on early wound signaling, I plan to explore some of these new areas, taking advantage of the R35’s flexible funding scheme.

项目概要 快速检测损伤并做出反应对于动物中所有生物体的生存至关重要。 伤口检测失败会导致急性和慢性疾病。 从愈合不良的伤口和感染到慢性皮肤发炎、纤维化和癌症。 伤口愈合的切割机制（涉及细胞因子、生长因子等）已被广泛研究， 它的启动机制仍然知之甚少，我的愿景是开发一种遗传和物理的方法。 伤口检测的简单模型最初对伤口的理解存在根本性的差距。 检测到，以及第一个伤口信号如何通过组织规模的传播快速传输损伤信息 与远处的白细胞、上皮细胞和其他参与愈合的细胞的关系。 我研究活体斑马鱼的伤口检测，斑马鱼的伤口反应和免疫系统与哺乳动物相似。 动物更适合在高动物吞吐量下进行高分辨率、实时成像。 实验室将内定量成像与无偏计算图像分析和各种跨学科相结合 十多年来，我已经确定了从生物物理学到数学建模的三种基本方法。 化学和一种物理伤口信号：过氧化氢 (H2O2)、细胞外 ATP (eATP)、花生四烯酸 （AA）和核膜张力。然而，这些发现引发了一个古老领域的新活动。 差距仍然存在：如何感知 eATP 来介导伤口快速闭合，以及它如何指示远处的细胞 尽管它会在组织中迅速分解并且无法扩散到远离伤口的地方，但 H2O2 和 AA 的效果如何？ 信号整合以介导伤口的快速炎症反应？伤口信号会引起炎症吗？ 他们还解决了这个问题吗？伤口机械传导在分子和细胞生物学水平上是如何调节的？ 这些问题具有很高的基本生物学意义，它们关注的途径是重大疾病的调控。 在未来五年内回答这些问题可以为新的治疗方法铺平道路。 我在伤口信号传导方面的工作为生物学的其他领域打开了大门，在这些领域中，类似的机制可能 驱动医学上重要的过程，例如感染反应、癌症和骨再生/重塑。 尽管我的小组的主要关注点仍然是早期伤口信号传导，但我计划探索其中的一些 新领域，利用 R35 灵活的资助计划。